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Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats.
Clin Exp Pharmacol Physiol. 2014 Sep; 41(9):698-707.CE

Abstract

The pacemaker current If conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays a critical role in the regulation of cardiac automaticity, with If density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective anti-arrhythmic agent, blocks human HCN currents and native If under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored If under after both acute (0.01, 0.1, 1, 10 and 100 μmol/L) and chronic (10 μmol/L) amiodarone treatment in ventricular myocytes from spontaneously hypertensive rats (SHR) with left ventricular hypertrophy using the whole-cell patch-clamp technique. The If current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control Wistar-Kyoto (WKY) rats. Acute application of amiodarone significantly decreased If density in myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC50 of 4.9 ± 1.2 and 6.9 ± 1.3 μmol/L in myocytes from SHR and WKY rats, respectively. Amiodarone increased the activation and deactivation times of If in myocytes from SHR, although it did not alter the relationship of voltage-dependent activation and the reversal potential of If in myocytes from SHR. Chronic exposure of myocytes from SHR to amiodarone potently inhibited If and downregulated HCN2 and HCN4, the major channel subtypes underlying native If , at both the mRNA and protein level. These findings indicate that amiodarone inhibits If under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of If currents; and (ii) indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its anti-arrhythmic properties under pathological conditions.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Li H
Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Zhou Y
No affiliation info available
Jiang B
No affiliation info available
Zhao X
No affiliation info available
Li X
No affiliation info available
Yang X
No affiliation info available
Jiang W
No affiliation info available

MeSH

AmiodaroneAnimalsBiological ClocksCell SeparationCells, CulturedDose-Response Relationship, DrugDown-RegulationElectric ConductivityHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsHypertrophy, Left VentricularMembrane PotentialsMyocytes, CardiacPotassium ChannelsPyrimidinesRatsRats, Inbred SHR

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24862298

Citation

Li, Hongxia, et al. "Dual Effects of Amiodarone On Pacemaker Currents in Hypertrophied Ventricular Myocytes Isolated From Spontaneously Hypertensive Rats." Clinical and Experimental Pharmacology & Physiology, vol. 41, no. 9, 2014, pp. 698-707.
Li H, Zhou Y, Jiang B, et al. Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 2014;41(9):698-707.
Li, H., Zhou, Y., Jiang, B., Zhao, X., Li, X., Yang, X., & Jiang, W. (2014). Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats. Clinical and Experimental Pharmacology & Physiology, 41(9), 698-707. https://doi.org/10.1111/1440-1681.12264
Li H, et al. Dual Effects of Amiodarone On Pacemaker Currents in Hypertrophied Ventricular Myocytes Isolated From Spontaneously Hypertensive Rats. Clin Exp Pharmacol Physiol. 2014;41(9):698-707. PubMed PMID: 24862298.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats. AU - Li,Hongxia, AU - Zhou,Yafeng, AU - Jiang,Bin, AU - Zhao,Xin, AU - Li,Xun, AU - Yang,Xiangjun, AU - Jiang,Wenping, PY - 2013/12/06/received PY - 2014/05/13/revised PY - 2014/05/15/accepted PY - 2014/5/28/entrez PY - 2014/5/28/pubmed PY - 2015/9/30/medline KW - amiodarone KW - hyperpolarization-activated cyclic nucleotide-gated channel KW - hypertrophied ventricular myocytes KW - pacemaker current If KW - spontaneously hypertensive rat KW - whole-cell patch-clamp techniques SP - 698 EP - 707 JF - Clinical and experimental pharmacology & physiology JO - Clin Exp Pharmacol Physiol VL - 41 IS - 9 N2 - The pacemaker current If conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays a critical role in the regulation of cardiac automaticity, with If density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective anti-arrhythmic agent, blocks human HCN currents and native If under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored If under after both acute (0.01, 0.1, 1, 10 and 100 μmol/L) and chronic (10 μmol/L) amiodarone treatment in ventricular myocytes from spontaneously hypertensive rats (SHR) with left ventricular hypertrophy using the whole-cell patch-clamp technique. The If current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control Wistar-Kyoto (WKY) rats. Acute application of amiodarone significantly decreased If density in myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC50 of 4.9 ± 1.2 and 6.9 ± 1.3 μmol/L in myocytes from SHR and WKY rats, respectively. Amiodarone increased the activation and deactivation times of If in myocytes from SHR, although it did not alter the relationship of voltage-dependent activation and the reversal potential of If in myocytes from SHR. Chronic exposure of myocytes from SHR to amiodarone potently inhibited If and downregulated HCN2 and HCN4, the major channel subtypes underlying native If , at both the mRNA and protein level. These findings indicate that amiodarone inhibits If under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of If currents; and (ii) indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its anti-arrhythmic properties under pathological conditions. SN - 1440-1681 UR - https://www.unboundmedicine.com/medline/citation/24862298/Dual_effects_of_amiodarone_on_pacemaker_currents_in_hypertrophied_ventricular_myocytes_isolated_from_spontaneously_hypertensive_rats_ DB - PRIME DP - Unbound Medicine ER -